Genetic Variability May Predict Severity of Side Effects From Methotrexate, A Common Chemotherapy Drug

DNA screening tool may be useful in tailoring treatments for cancer and other diseases

SEATTLE — June 25, 2001 — Nearly half of all Americans carry a genetic mutation that to some degree interferes with their ability to metabolize folate, a B vitamin found in fruits, grains, and dark green, leafy vegetables. Also available in supplement form as folic acid, this important nutrient perhaps is best known for its role in preventing birth defects in the brain and nervous system.

People with sluggish folate metabolism in general are at no greater risk for disease than the rest of the population. However, when exposed to a poor diet or certain drugs, these people can suffer significant clinical consequences, particularly if they are among the approximately 10 percent of Americans born with the most limited ability to process this nutrient.

Cornelia Ulrich, Ph.D., and colleagues from the Fred Hutchinson Cancer Research Center will report these findings in the July 1 issue of Blood. The study involved researchers from the Hutchinson Center's Public Health Sciences and Clinical Research divisions, as well as the University of Washington schools of Medicine, Dentistry, and Public Health and Community Medicine. Funding for this pilot study was provided by an interdisciplinary support grant from the National Cancer Institute.

The retrospective analysis involved 220 bone-marrow transplant patients who received methotrexate, an antifolate drug used as standard therapy for preventing graft-vs-host disease, a common complication of marrow transplantation. In analyzing the patients' stored DNA, Ulrich and colleagues found that those with the lowest activity of a key folate-metabolizing enzyme (called methylenetetrahydrofolate reductase, or MTHFR) suffered the highest degree of toxicity and treatment complications.

Side effects of methotrexate include oral mucositis and delayed blood-platelet recovery. Oral mucositis is characterized by a painful inflammation of the tissues lining the mouth, throat and gastrointestinal tract; delayed platelet recovery can interfere with blood clotting and require expensive platelet transfusions.

Patients with two copies of the MTHFR variant had less than half the rate of folate-enzyme activity as compared to those with only one copy of the mutation, resulting in a 36 percent increase in oral mucositis symptoms and a 34 percent slower recovery of platelet counts. This is the first study of its kind to show the impact of this genetic variant on drug response.

"Oral mucositis is one of the worst side effects of marrow transplantation from the patient's perspective because it interferes with their eating, drinking, talking, and sometimes even breathing. It also increases the risk of infection as well as the cost and duration of the hospital stay," said Ulrich, an assistant member of the Hutchinson Center's Public Health Sciences Division and a research assistant professor of epidemiology at the UW.

In addition to preventing graft-vs.-host-disease in marrow-transplant patients, methotrexate is used to treat certain cancers and, in lower doses, immune diseases such as rheumatoid arthritis. The drug works by temporarily interfering with the body's use of folic acid, a nutrient needed for cell growth.

The reason patients with the MTHFR gene mutation suffer more severe side effects of antifolate chemotherapy, Ulrich hypothesizes, is because their bodies lack the adequate folate necessary to produce nucleotides — a key component of the DNA-repair machinery. Patients with variations in the MTHFR gene, in the future, may be candidates for more customized therapy, from altered dosages to alternative drugs.

"We know that every patient reacts somewhat differently to the drugs they're given and, until recently, our ability to understand how a patient will react has been very limited, based on characteristics like age and body weight," Ulrich said. "Now, with our increasing understanding of genetics, we can better predict how patients will process a drug and thus provide the appropriate dose for that patient. Ultimately this will allow us to tailor our drug dosages to reduce toxicity, or side effects, and increase effectiveness."

Ulrich next plans to study the effects of this variant on graft-vs-host disease, as well as the effects of other genetic alterations in folate metabolism. "If these results are confirmed by further research," Ulrich said, "then testing people for this common genetic variant may become a cost-effective strategy for customizing treatment based on a patient's unique genetic makeup."

Editor's Note
For a copy of the paper, "Pharmacogenetics of Methotrexate…" by Ulrich and colleagues (Blood, July 1, 2001, Vol. 98, No. 1), please contact Margo Meyerhoff at the journal, (202) 776-0550 or mmeyerhoff@hematology.org.

Fred Hutchinson Cancer Research Center
Fred Hutchinson Cancer Research Center, home of three Nobel laureates, is an independent, nonprofit research institution dedicated to the development and advancement of biomedical technology to eliminate cancer and other potentially fatal diseases. Recognized internationally for its pioneering work in bone-marrow transplantation, the center's four scientific divisions collaborate to form a unique environment for conducting basic and applied science. Fred Hutchinson, in collaboration with its clinical and research partners, UW Medicine and Children's Hospital and Regional Medical Center, is the only National Cancer Institute-designated comprehensive cancer center in the Pacific Northwest and is one of 40 nationwide. For more information, visit the center's website at www.fhcrc.org.

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